title: The aggregation-enhancing huntingtin N-terminus is helical in amyloid fibrils.
abstract: The 17-residue N-terminus (htt(NT)) directly flanking the polyQ sequence in huntingtin (htt) N-terminal fragments plays a crucial role in initiating and accelerating the aggregation process that is associated with Huntington's disease pathogenesis. Here we report on magic-angle-spinning solid-state NMR studies of the amyloid-like aggregates of an htt N-terminal fragment. We find that the polyQ portion of this peptide exists in a rigid, dehydrated amyloid core that is structurally similar to simpler polyQ fibrils and may contain antiparallel β-sheets. In contrast, the htt(NT) sequence in the aggregates is composed in part of a well-defined helix, which likely also exists in early oligomeric aggregates. Further NMR experiments demonstrate that the N-terminal helical segment displays increased dynamics and water exposure. Given its specific contribution to the initiation, rate, and mechanism of fibril formation, the helical nature of htt(NT) and its apparent lack of effect on the polyQ fibril core structure seem surprising. The results provide new details about these disease-associated aggregates and also provide a clear example of an amino acid sequence that greatly enhances the rate of amyloid formation while itself not taking part in the amyloid structure. There is an interesting mechanistic analogy to recent reports pointing out the early-stage contributions of transient intermolecular helix-helix interactions in the aggregation behavior of various other amyloid fibrils.
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: V N
authors.initials: VN
authors.lastname: Sivanandam
authors.forename: Murali
authors.initials: M
authors.lastname: Jayaraman
authors.forename: Cody L
authors.initials: CL
authors.lastname: Hoop
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kodali
authors.forename: Ronald
authors.initials: R
authors.lastname: Wetzel
authors.forename: Patrick C A
authors.initials: PC
authors.lastname: van der Wel
mesh_terms: D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000592:standards; D008958:Models, Molecular; D010316:Particle Size; D017433:Protein Structure, Secondary; D012015:Reference Standards; D013499:Surface Properties
chemical_list: D016229:Amyloid beta-Peptides